Question 1. When should ABL kinase domain mutation testing be considered for a patient with chronic myelogenous leukemia (CML)?

The National Comprehensive Cancer Network (NCCN)1 recommends ABL mutation testing when there is:

Inadequate initial response to TKI therapy

Loss of hematologic or cytogenetic remission

Rise in BCR-ABL1 transcript by 1 log over at least 2 time points, resulting in loss of major molecular remission

Progression to accelerated or blast phase

Mutation testing is not recommended in newly diagnosed chronic phase patients or during routine monitoring.

Question 2. How are ABL kinase domain mutations detected?

RNA is isolated from blood or bone marrow and reverse transcribed. A first round of PCR selectively amplifies BCR-ABL1 fusion product in CML cells. A second round of PCR then amplifies the ABL kinase domain, which is directly sequenced.

Question 3. Which ABL kinase domain mutations are detected?

All of the >90 clinically relevant mutations in the BCR-ABL kinase domain are detected in this assay. This includes the pan-resistant T315I mutation.

Question 4. What is the clinical significance of specific mutations?

The resistance pattern varies among the different mutations.2 For example, patients with the T315I mutation can respond to ponatinib3 but not to other FDA-approved tyrosine kinase inhibitors. Patients with V299L, T315A, or F317L/V/I/C mutations may respond to nilotinib therapy, whereas those with Y253H, E255K/V, or F359 V/C/I may respond to dasatinib.

When we report the specific mutation detected, we will provide information about commonly observed kinase inhibitor reactions (response vs resistance) associated with that mutation.

Question 5. What if my patient is resistant to therapy but no mutations are detected?

Mutations in the ABL kinase domain play a role in about 50% of CML cases with secondary TKI resistance. Other mechanisms include altered drug transport and metabolism, amplification of the Philadelphia chromosome, and acquisition of additional chromosomal abnormalities. To evaluate the patient for the latter two, consider ordering these tests:

FISH, CML/ALL, BCR-ABL, Translocation 9;22 (test code 12070X)

Chromosome Analysis, Hematologic Malignancy (test code 14600X)

Question 6. What is the role of ABL mutation testing in patients with acute lymphoblastic leukemia (ALL)?

TKIs are combined with chemotherapy to treat lymphoblastic leukemias and lymphomas (ALL/LBL) that have t(9;22)/BCR-ABL rearrangements. ABL kinase domain mutations, particularly T315I, F317L, and Y253H, are frequently present in ALL/LBL patients who lack initial response or who relapse. Identification of the particular resistance-causing mutation(s) can help guide therapy for such patients.4

This FAQ is provided for informational purposes only and is not intended as medical advice. A clinician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.